Similar to peptides, oligonucleotides, and oligosaccharides, most small molecule natural products are highly modular in their constitution. This is because, like the aforementioned oligomers, the majority of small molecules are biosynthesized via the sequential coupling of bifunctional building blocks. Specifically, polyketides are derived from multiple malonyl-CoA and/or methmalonyl-CoA units, non-ribosomal peptides are built from amino acids, polyterpenes are stitched together from isopentenyl pyrophosphate and/or dimethylallyl pyrophosphate building blocks, and fatty acids are prepared from fragments of malonyl-CoA. Other classes of modular natural products result from the oxidative coupling of common building blocks, such as shikimic acid, amino acids, and/or their respective derivatives.
With peptides, oligonucleotides, and increasingly oligosaccharides, this inherent modularity is now routinely harnessed to enable fully automated syntheses from suitably protected bifunctional building blocks (R. B. Merrifield, Science 1965, 150, 178-185; M. H. Caruthers, Science 1985, 24, 799; and O. J. Plante, M. R. Palmacci, P. H. Seeberger, Science 2001, 291, 1523). As a direct result of these advances, research in theses areas is primarily focused on discovering and understanding new molecular function. In stark contrast, despite tremendous advances over the course of nearly two centuries, the laboratory synthesis of small molecules remains a relatively complex, inflexible, and non-systematized process practiced almost exclusively by highly-trained specialists. (For pioneering developments in the automated synthesis of small molecules via polymer-assistance and/or flow chemistry, see: a) C. H. Hornung, M. R. Mackley, I. R. Baxendale and S. V. Ley and, Org. Proc. Res. Dev. 2007, 11, 399-405; b) Nikzad Nikbin, Mark Ladlow, and Steven V. Ley Org. Process Res. Dev. 2007, 11, 458-462; and c) France, S.; Bernstein, D.; Weatherwax, A.; Lectka, T. Org. Lett. 2005, 7, 3009-3012.) Thus, research in this area is still heavily weighted towards synthesis. Given the special properties of many small molecules that make them uniquely suited for a wide range of applications in science, engineering, and medicine, increased access to these compounds via a highly general and automated synthesis platform that is accessible to the non-expert would be highly enabling. Ultimately, such a process could help shift the primary focus from the synthesis of small molecules to the discovery and understanding of important small molecule functions.